rs759557477

Variant names:

• chr11-68043825-A-G
• rs759557477
• NM_006019.4:c.725A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006019.4(TCIRG1):​c.725A>G​(p.His242Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,411,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H242Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TCIRG1 NM_006019.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.14
• Publications: 3 publications found

Genes affected

TCIRG1 (HGNC:11647): (T cell immune regulator 1, ATPase H+ transporting V0 subunit a3) This gene encodes a subunit of a large protein complex known as a vacuolar H+-ATPase (V-ATPase). The protein complex acts as a pump to move protons across the membrane. This movement of protons helps regulate the pH of cells and their surrounding environment. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. V-ATPase is comprised of a cytosolic V1 domain and a transmembrane V0 domain. Alternative splicing results in multiple transcript variants. Mutations in this gene are associated with infantile malignant osteopetrosis. [provided by RefSeq, May 2017]

TCIRG1 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet
• autosomal recessive osteopetrosis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal dominant severe congenital neutropenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive osteopetrosis 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dysosteosclerosis

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006019.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	NM_006019.4	MANE Select	c.725A>G	p.His242Arg	missense	Exon 8 of 20	NP_006010.2
	TCIRG1	NM_001440552.1		c.725A>G	p.His242Arg	missense	Exon 9 of 21	NP_001427481.1
	TCIRG1	NM_001440553.1		c.725A>G	p.His242Arg	missense	Exon 8 of 20	NP_001427482.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	ENST00000265686.8	TSL:1 MANE Select	c.725A>G	p.His242Arg	missense	Exon 8 of 20	ENSP00000265686.3
	TCIRG1	ENST00000532635.5	TSL:1	c.77A>G	p.His26Arg	missense	Exon 3 of 15	ENSP00000434407.1
	TCIRG1	ENST00000698255.1		c.674A>G	p.His225Arg	missense	Exon 8 of 20	ENSP00000513630.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000584 AC: 1 AN: 171270 AF XY: 0.0000109

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000783

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1411252 Hom.: 0 Cov.: 33 AF XY: 0.00000287 AC XY: 2 AN XY: 697536

African (AFR) AF: 0.00 AC: 0 AN: 32224

American (AMR) AF: 0.00 AC: 0 AN: 37104

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25296

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36948

South Asian (SAS) AF: 0.00 AC: 0 AN: 80256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086666

Other (OTH) AF: 0.00 AC: 0 AN: 58516

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000847 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive osteopetrosis 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.090	D
PhyloP100		3.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.72
Sift	Benign	0.038	D
Sift4G	Benign	0.21	T
Polyphen		0.98	D
Vest4		0.76
MutPred		0.50		Gain of MoRF binding (P = 0.0461)
MVP		0.96
MPC		0.41
ClinPred		0.76	D
GERP RS		5.4
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.60
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs759557477; hg19: chr11-67811292; COSMIC: COSV55835327; COSMIC: COSV55835327;